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Leukemia stem cells niche normal hematopoiesis

Andi Wang, Hua Zhong
OBJECTIVES: To summarize the effects of the bone marrow niche on hematopoiesis and leukemogenesis and discuss the chemotherapy resistance that can arise from interactions between the niche and leukemia stem cells. METHODS: We review the major roles of the bone marrow niche in cell proliferation, adhesion and drug resistance. The signaling pathways and major molecular participants in the niche are discussed. We also address potential niche-targeting strategies for the treatment of acute myeloid leukemia (AML)...
June 14, 2018: Hematology (Amsterdam, Netherlands)
Noboru Asada
Hematopoietic stem cells (HSCs) that give rise to all kinds of hematopoietic lineage cells on various demands throughout life are maintained in a specialized microenvironment called "niche" in the bone marrow (BM). Defining niche cells and unveiling its function have been the subject of intense study, and it is becoming increasingly clear how niche cells regulate HSCs in normal hematopoiesis. Leukemia stem cells (LSCs), which are able to produce leukemic cells and maintain leukemic clones, are assumed to share common features with healthy HSCs...
2018: Frontiers in Oncology
Graça Almeida-Porada, Christopher Rodman, Bradford Kuhlman, Egil Brudvik, John Moon, Sunil George, Peter Guida, Satria P Sajuthi, Carl D Langefeld, Stephen J Walker, Paul F Wilson, Christopher D Porada
The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated...
April 26, 2018: Stem Cells and Development
Pingnan Xiao, Monika Dolinska, Lakshmi Sandhow, Makoto Kondo, Anne-Sofie Johansson, Thibault Bouderlique, Ying Zhao, Xidan Li, Marios Dimitriou, George Z Rassidakis, Eva Hellström-Lindberg, Nagahiro Minato, Julian Walfridsson, David T Scadden, Mikael Sigvardsson, Hong Qian
Mutations of signal-induced proliferation-associated gene 1 ( SIPA1 ), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis...
March 13, 2018: Blood Advances
Peng Zhang, Zizhen Chen, Rong Li, Ying Guo, Hui Shi, Jie Bai, Hui Yang, Mengyao Sheng, Zhaomin Li, Zhuo Li, Jianping Li, Shi Chen, Weiping Yuan, Tao Cheng, Mingjiang Xu, Yuan Zhou, Feng-Chun Yang
Somatic or de novo mutations of Additional sex combs-like 1 ( ASXL1 ) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1 , which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias...
2018: Cell Discovery
Stefan Habringer, Constantin Lapa, Peter Herhaus, Margret Schottelius, Rouzanna Istvanffy, Katja Steiger, Julia Slotta-Huspenina, Andreas Schirbel, Heribert Hänscheid, Stefan Kircher, Andreas K Buck, Katharina Götze, Binje Vick, Irmela Jeremias, Markus Schwaiger, Christian Peschel, Robert Oostendorp, Hans-Jürgen Wester, Götz-Ulrich Grigoleit, Ulrich Keller
C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance. Methods: We used patient-derived (PDX) and cell line-based xenograft mouse models of ALL and AML to evaluate the efficacy and toxicity of a CXCR4-targeted endoradiotherapy (ERT) theranostic approach...
2018: Theranostics
Delfim Duarte, Edwin D Hawkins, Olufolake Akinduro, Heather Ang, Katia De Filippo, Isabella Y Kong, Myriam Haltalli, Nicola Ruivo, Lenny Straszkowski, Stephin J Vervoort, Catriona McLean, Tom S Weber, Reema Khorshed, Chiara Pirillo, Andrew Wei, Saravana K Ramasamy, Anjali P Kusumbe, Ken Duffy, Ralf H Adams, Louise E Purton, Leo M Carlin, Cristina Lo Celso
Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand...
January 4, 2018: Cell Stem Cell
Marta Galán-Díez, Álvaro Cuesta-Domínguez, Stavroula Kousteni
Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells...
September 29, 2017: Cold Spring Harbor Perspectives in Medicine
Allison J Li, Laura M Calvi
Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression...
November 2017: Experimental Hematology
B Kumar, M Garcia, L Weng, X Jung, J L Murakami, X Hu, T McDonald, A Lin, A R Kumar, D L DiGiusto, A S Stein, V A Pullarkat, S K Hui, N Carlesso, Y-H Kuo, R Bhatia, G Marcucci, C-C Chen
Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth...
March 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Juan Carlos Balandrán, Eduardo Vadillo, David Dozal, Alfonso Reyes-López, Antonio Sandoval-Cabrera, Merle Denisse Laffont-Ortiz, Jessica L Prieto-Chávez, Armando Vilchis-Ordoñez, Henry Quintela-Nuñez Del Prado, Héctor Mayani, Juan Carlos Núñez-Enríquez, Juan Manuel Mejía-Aranguré, Briceida López-Martínez, Elva Jiménez-Hernández, Rosana Pelayo
BACKGROUND AND AIMS: Childhood acute leukemias (AL) are characterized by the excessive production of malignant precursor cells at the expense of effective blood cell development. The dominance of leukemic cells over normal progenitors may result in either direct suppression of functional hematopoiesis or remodeling of microenvironmental niches, contributing to BM failure and AL-associated mortality. We undertook this study to investigate the contents and functional activity of hematopoietic stem/progenitor cells (HSPC) and their relationship to immune cell production and risk status in AL pediatric patients...
November 2016: Archives of Medical Research
Marco Carretta, Bauke de Boer, Jenny Jaques, Antonella Antonelli, Sarah J Horton, Huipin Yuan, Joost D de Bruijn, Richard W J Groen, Edo Vellenga, Jan Jacob Schuringa
Recently, NOD-SCID IL2Rγ-/- (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO)...
July 2017: Experimental Hematology
Kazuhito Naka, Atsushi Hirao
Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) maintain the homeostasis of normal hematopoiesis through the precise generation of mature blood cells. Numerous genetic studies in mice have shown that stem-cell quiescence is critical for sustaining primitive long-term HSCs in vivo. In this review, we first examine the crucial roles of transforming growth factor β (TGF-β) and related signaling molecules in not only regulating the well-known cytostatic effects of these molecules but also governing the self-renewal capacity of HSCs in their in vivo microenvironmental niche...
September 1, 2017: Cold Spring Harbor Perspectives in Biology
Hind Medyouf
Similar to their healthy counterpart, malignant hematopoietic stem cells in myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia, reside in a highly complex and dynamic cellular microenvironment in the bone marrow. This environment provides key regulatory signals for and tightly controls cardinal features of hematopoietic stem cells (HSCs), including self-renewal, quiescence, differentiation, and migration. These features are essential to maintaining cellular homeostasis and blood regeneration throughout life...
March 23, 2017: Blood
Ander Abarrategi, Katie Foster, Ashley Hamilton, Syed A Mian, Diana Passaro, John Gribben, Ghulam Mufti, Dominique Bonnet
The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs. Scaffolds coated with human mesenchymal stromal cells (hMSCs) proved to be superior in terms of HSC engraftment and long-term maintenance when implanted in vivo...
February 1, 2017: Journal of Clinical Investigation
Jennifer Enciso, Hector Mayani, Luis Mendoza, Rosana Pelayo
Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis...
2016: Frontiers in Physiology
Christine Roden, Jun Lu
Studies on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have helped to establish the paradigms of normal and cancer stem cell concepts. For both HSCs and LSCs, specific gene expression programs endowed by their epigenome functionally distinguish them from their differentiated progenies. MicroRNAs (miRNAs), as a class of small non-coding RNAs, act to control post-transcriptional gene expression. Research in the past decade has yielded exciting findings elucidating the roles of miRNAs in control of multiple facets of HSC and LSC biology...
September 2016: Current Stem Cell Reports
Lisa Pleyer, Peter Valent, Richard Greil
Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts...
June 27, 2016: International Journal of Molecular Sciences
Hui Cheng, Tao Cheng
PURPOSE OF REVIEW: Mortality and morbidity associated with leukemia are largely due to frequently occurring cytopenias or the dysfunction of normal blood cells in patients. Our knowledge of how normal blood cells degenerate in response to leukemic cell infiltration has been quite limited. This review summarizes recent findings and discusses both extrinsic and intrinsic mechanisms underlying the suppression of normal hematopoiesis in leukemia. RECENT FINDINGS: Recent studies have shown that leukemic cells are able to remodel the bone marrow niche by secreting specific cytokines or dampening its hematopoietic-supporting functions...
July 2016: Current Opinion in Hematology
Jing Li, Jun Zhang, Minghui Tang, Junping Xin, Yan Xu, Andrew Volk, Caiqin Hao, Chenglong Hu, Jiewen Sun, Wei Wei, Quichan Cao, Peter Breslin, Jiwang Zhang
The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs...
August 2016: Stem Cells
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